Project Summary The goal of this research proposal is to elucidate the mechanisms that regulate sister telomere cohesion in human cells. Telomeres are unique heterochromatic structures that require specialized mechanisms for their replication, protection, and cohesion. Establishment of cohesion between sister telomeres in S phase is essential for homologous recombination and DNA repair in G2 phase of the cell cycle and timely resolution of cohesion between sister telomeres at mitosis is critical for genome integrity. Our studies in human cells have shown that sister telomeres require distinct mechanisms (compared to sister arms and centromeres) for cohesion establishment in S phase and resolution in mitosis. Here we seek to elucidate the underlying mechanisms. In Aim 1 we will determine how cohesion is established at telomeres and why it is important. In Aim 2 we will determine how cohesion is removed from telomeres at mitosis and what happens if it is not. And in Aim 3 we will explore a novel hypothesis (based upon our new preliminary data) that persistent cohesion at mitosis is a general cellular mechanism for dealing with telomere dysfunction. ! PUBLIC HEALTH RELEVANCE: Project Narrative Telomeres, the ends of chromosomes, play a crucial role in chromosome stability and genome integrity. Telomere dysfunction contributes to aging, cancer, and other human diseases, including dyskeratosis congenital an inherited bone marrow failure disease. The results from this project will reveal how telomere function is maintained in human cells and will thus impact our understanding of human disease and contribute to therapeutics in cancer and aging.